Compositions and method for the sublingual or buccal administration therapeutic agents

ABSTRACT

Pharmaceutical compositions for the sublingual or buccal administration of therapeutic agents which are normally degraded upon oral administration comprise such a therapeutic agent, a solvent, optionally a cosolvent and/or hydrogel, and an oral mucosal membrane transport enhancing agent which is selected from the group consisting of essential and volatile oils and inorganic and organic acids.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.07/983,111, filed Nov. 30, 1992, now U.S. Pat. No. 5,284,657 which, inturn, is a continuation of application Ser. No. 07/750,843 filed Aug.26, 1991, now abandoned.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions and amethod of using such compositions. More particularly, the presentinvention concerns pharmaceutical compositions useful for the sublingualor buccal administration of oligopeptides of twenty aminoacyl residuesor less and to a method of using such compositions.

BACKGROUND OF THE INVENTION

A number of naturally-occuring peptides of twenty aminoacyl residues orless have important pharmacological properties. Recent pharmaceuticalresearch has also led to the discovery of many synthetic ornon-naturally occuring peptides in this class which are effectivetherapeutic agents. Noteworthy among these synthetic small peptides arecompounds which act as either agonists or as antagonists of gonadotropinreleasing hormone (GnRH, also known as "luteininzing hormone releasinghormone, LHRH), and peptides or pseudo-peptides of twenty residues orless which act to inhibit renin and are thus effective as agents fortreating hypertension and related disease conditions of thecardiovascular system. A number of small peptides and modified peptideshave also been found which act to modulate the natural peptide C5a.

While the discovery of peptide compounds having therapeutic value hasmoved rapidly in the last few years, the development of viable drugdelivery systems for many of these compounds has often provedproblematic. Most, if not all, of these compounds must be administeredparenterally as, for example, by subcutaneous, intramuscular orintrapertoneal injection. Since most patients cannot self-administerparenteral drug formulations, it is frequently necessary that drugs ofthis type be administered in an out-patient setting leading toadditional costs associated with their use. Administration of most ofthese compounds by an oral route, although more convenient, has notgenerally been available. Orally administered therapeutic agents arerapidly transported to the stomach and small intestine for absorptionacross gastro-intestinal mucosal membranes into the blood. Theefficiency of absorption of a therapeutic agent (i.e. the ratio of theamount entering the blood to the mount administered) following oraladministration of many drugs can be low because of several factors whichserve to metabolize the administered chemical. Low absorption efficiencyis particularly problematic with polypeptide therapeutic agents.

The gastrointestinal tract secretes a variety of agents that metabolizepolypeptides. Exemplary of such catabolic agents are pepsin, trypsin,chymotrypsin, carboxypolypeptidases, aminopolypeptidases anddipeptidases. Polypeptides that escape catabolism in the stomach andsmall intestine are transported across the cells lining thegastrointestinal tract into the portal circulation, which carriesabsorbed polypeptides to the liver. Absorbed polypeptides are subject tofurther degradation by a myriad of hepatic metabolic events. Suchhepatic degradation of absorbed materials from the blood before suchmaterials enter the general systemic circulation is known in thepharmaceutical art as the "first pass effect".

As a result of these factors causing low absorptive efficiency of orallyadministered therapeutic agents, particularly polypeptides, if thechoice of the route of administration is the oral route, it is necessaryto administer large dosages of such polypeptides. This is costly in manycases and inefficient. Alternatively, such therapeutic agents can beadministered via other routes such as intravenously, subcutaneously orintraperitoneally. These alternate routes are all invasive by nature andcan involve pain and discomfort to a subject. There is, therefore, apressing need for new, efficient, cost-effective and non-invasivemethods and compositions for the administration to patients oftherapeutic agents which would be otherwise degraded if administeredorally.

The present invention provides novel compositions and methods for theoral administration of peptide therapeutic agents.

BRIEF DESCRIPTION OF THE DRAWINGS In the drawings, which form a part ofthis disclosure:

FIG. 1 is a plot of plasma leuprolide concentration vs. time followingthe sublingual administration of seven (A-G) different liquidcompositions containing 50 mg/ml of the leutenizing hormone releasinghormone (LHRH) agent leuprolide acetate. Anesthetized dogs wereadministered 0.1 ml/10 kg body wt of compositions A-G of Table 1 and theplasma levels of leuprolide determined by RIA at the indicated times.

FIG. 2 is a plot of plasma leuprolide concentration vs. time followingthe sublingual administration of liquid compositions comprising 2.5percent by weight Klucel LF™, an aqueous-alcohol solvent having 0percent (EtOH:H20 0:100), 50 percent (EtOH:H₂ 0 50:50) 65 percent(EtOH:H₂ 0 65:35) or 80 (EtOH:H₂ 0 80:20) by volume ethanol (EtOH). Thedose of administered leuprolide acetate and the measurement of plasmaleuprolide concentration are the, same as described for FIG. 1.

FIG. 3 is a plot of plasma leuprolide concentration vs. time followingthe sublingual administration of a liquid composition comprising 50mg/ml leuprolide acetate, 2.5 percent by weight hydroxypropylmethylcellulose (HPMC), an aqueous-alcohol solvent having 80 percent by volumeethanol and 0,5 or 10 percent by weight benzoic acid. The dose ofadministered leuprolide acetate mid the measurement of plasma leuprolideconcentration are the same as described for FIG. 1.

FIG. 4 is a bar graph of area under the curve (AUC 0-8 hours) vs.peppermint oil concentration (percent by volume). Dogs were sublinguallyadministered 0.1 ml/10 kg body weight of a liquid composition comprising50 mg/ml leuprolide acetate, an aqueous-alcohol solvent having 80percent by volume ethanol and 0, 0.5, 2.0, 2.5, 5 or 10 percent byvolume peppermint oil.

BRIEF SUMMARY OF THE INVENTION

In its principal aspect, the present invention provides liquidcompositions for the sublingual or buccal administration of peptide andpseudo-peptide therapeutic agents of twenty residues or less which arenormally degraded upon oral administration, comprising the therapeuticagent and a carrier which comprises a solvent system and an oral mucosalmembrane transport enhancing agent. The solvent system comprises analcohol which is from about 20 percent to about 95 percent w/v of thetotal volume of the carrier. The balance of the carrier comprises fromabout 0.5 percent w/v to about 20 percent w/v, based upon the totalvolume of the carrier, of a mucosal membrane transport enhancing agentand, optionally, a cosolvent and/or a hydrogel. The cosolvent, whenpresent, comprises from about 5 percent w/v to about 80 percent w/v ofthe carrier, and the optional hydrogel, when present, comprises fromabout 1 percent w/v to about 5 percent w/v of the carrier. The oralmucosal membrane transport enhancing agent is selected from the groupconsisting of essential and volatile oils and pharmaceuticallyacceptable, non-toxic inorganic or organic acids, and comprises betweenabout 0.5 percent w/v and 50 percent w/v of the carrier.

In another aspect, the present invention provides a method for thesublingual or buccal administration of a therapeutic agent, particularlya polypeptide of twenty aminoacyl residues or less, to a patientcomprising preparing a liquid composition of this invention andadministering said liquid composition under the tongue of the patient.

DETAILED DESCRIPTION OF THE INVENTION

The liquid compositions of the present invention are particularly suitedfor the sub-lingual or buccal administration of peptide orpseudo-peptide therapeutic agents of twenty residues or less, which arenormally degraded upon oral administration. As used herein, the term"pseudo-peptide" means a compound comprising a sequence of twenty aminoacid residues or less connected by peptide linkages in which one or moreof the aminoacyl units may comprise a non-naturally-occuring amino acidor a naturally-occuring amino acid which has a modified alphaside-chain.. Preferably, polypeptides used in the present invention aredrugs, medicaments and other agents having a pharmacological orphysiological action in an animal subject to affect lutenizing hormonereleasing hormone (LHRH), to inhibit the action of renin, or to modulatethe physiological activity of C5a..

The preparation and therapeutic use of suitable peptide agonists andantagonists of gonadotropin releasing hormone (GnRH, also known asluteinizing hormone releasing hormone, LHRH) comprising from three toten aminoacyl residues for incorporation into sublingual formulations inaccordance with the present invention are disclosed in the followingUnited States Patents which are incorporated herein by reference:

1. Folkers, et al., U.S. Pat. No. 3,787,385, issued Jan. 22, 1974;

2. Flouret, et at., U.S. Pat. No. 3,790,555, issued Feb. 8, 1974;

3. Flouret, U.S. Pat. No. 3,826,794, issued Jul. 30, 1974;

4. Fujino, et al., U.S. Pat. No. 3,853,837, issued Dec. 10, 1974;

5. Sakakibara, et al., U.S. Pat. No . 3,880,825, issued Apr. 29, 1975;

6. Shields, U.S. Pat. No. 3,915,947, issued Oct. 28, 1975;

7. Folkers, et al., U.S. Pat. No. 3,953,416, issued Apr. 27, 1976;

8. Hoffmann, et al., U.S. Pat. No. 3,963,691, issued Jun. 15, 1976;

9. Folkers, et al., U.S. Pat. No. 3,974,135, issued Aug. 10, 1976;

10. Koenig, et al., U.S. Pat. No. 4,003,884, issued Jan. 18, 1977;

11. Fujino, et al., U.S. Pat. 4,008,209, issued Feb. 15, 1977;

12. Tinney, et al., U.S. Pat. No. 4,022,759, issued May 10, 1977;

13. Tinney, U.S. Pat. No. 4,022,760, issued May 10, 1977;

14. Tinney, et al., U.S. Pat. No. 4,022,761, issued May 10, 1977;

15. Johnson, et al., U.S. Pat. No. 4,071,622, issued Jan. 31, 1978;

16. Koenig, U.S. Pat. No. 4,024,248, issued May 17, 1977;

17. Amoss, et al., U.S. Pat. No. 4,072,668, issued Feb. 7, 1978;

18. Tinney, U.S. Pat. No. 4,075,189, issued Feb. 21, 1978;

19. Nicolaides, U.S. Pat. No. 4,075,192, issued Feb. 21, 1978;

20. Tinney, U.S. Pat. No. 4,087,419, issued May 2, 1978;

21. Foel, et al., U.S. Pat. No. 4,089,946, issued May 16, 1978;

22. Dutta, et al., U.S. Pat. No. 4,100,274 issued Jul. 11, 1978;

23. Moody, U.S. Pat. No. 4,128,638, issued Dec. 5, 1978;

24. Fujino, et al., U.S. Pat. No. 4,229,438, issued Oct. 21, 1980;

25. Nestor, et al., U.S. Pat. No. 4,234,571, issued Nov. 18, 1980;

26. Rivier, et al., U.S. Pat. No. 4,244,946, issued Jan. 13, 1981;

27. Sarantakis, U.S. Pat. No. 4,253,997, issued Mar. 3, 1981;

28. Coy, et al.,, et al., U.S. Pat. No. 4,317,815, issued Mar. 2, 1982;

29. Nestor, et al., U.S. Pat. No. 4,318,905, issued Mar. 9, 1982;

30. Nestor, et al., U.S. Pat. No. 4,341,767, issued Jul. 27, 1982;

31. Veber, et al., U.S. Pat. No. 4,377,515, issued Mar. 22, 1983;

32. Rivier, et al., U.S. Pat. No. 4,382,922, issued May 10, 1983;

33. Rivier, et al., U.S. Pat. No. 4,409,208, issued Oct. 11, 1983;

34. Vail, Jr., et al., U.S. Pat. No. 4,410,514, issued Oct. 18, 1983;

35. Nestor, et al., U.S. Pat. No. 4,419,347, issued Dec. 6, 1983;

36. Sherwood, et al., U.S. Pat. No. 4,443,368, issued Apr. 17, 1984;

37. Rivier, et al., U.S. Pat. No. 4,444,759, issued Apr. 24, 1984;

38. Nestor, et al., U.S. Pat. No. 4,481,190, issued Nov. 6, 1984;

39. Folkers, et al., U.S. Pat. No. 4,504,414, issued Mar. 12, 1985;

40. Nestor, et al., U.S. Pat. No. 4,530,920, issued Jul. 23, 1985;

41. Roeske, U.S. Pat. No. 4,547,370, issued Oct. 15, 1985;

42. Antoni, et at., U.S. Pat. No. 4,552,864, issued Nov. 12, 1985;

43. Rivier, et al., U.S. Pat. No. 4,565,804, issued Jan. 21, 1986;

44. Rivier, et al., U.S. Pat. No. 4,569,927, issued Feb. 11, 1986;

45. Seproedi, et al., U.S. Pat. No. 4,600,705, issued Jul. 15, 1986;

46. Mia, U.S. Pat. No. 4,608,251, issued Aug. 26, 1986;

47. Vale, Jr., et al., U.S. Pat. No. 4,619,914, issued Oct. 28, 1986;

48. Folkers, et al., U.S. Pat. No. 4,642,332, issued Feb. 10, 1987;

49. Gulyas, et al., U.S. Pat. No. 4,647,553, issued Mar. 3, 1987;

50. Rivier, et al., U.S. Pat. No. 4,652,550, issued Mar. 24, 1987;

51. Folkers, et al., U.S. Pat. No. 4,656,247, issued Apr. 7, 1987;

52. Rivier, et al., U.S. Pat. No. 4,661,472, issued Apr. 28, 1987;

53. Nestor, et at., U.S. Pat. No. 4,667,014, issued May 10, 1987;

54. Rivier, et al., U.S. Pat. No. 4,677,193, issued Jun. 30, 1987;

55. Roeske, et al., U.S. Pat. No. 4,689,396, issued Aug. 25, 1987;

56. Nestor, et al., U.S. Pat. No. 4,690,916, issued Sep. 1, 1987;

57. Uhmann, et al., U.S. Pat. No. 4,691,008, issued Sep. 1, 1987;

58. Folkers, et at., U.S. Pat. No. 4,721,775, issued Jan. 26, 1988;

59. Schally, et al., U.S. Pat. No. 4,725,577, issued Feb. 16, 1988;

60. Vale, Jr., et al., U.S. Pat. No. 4,740,500, issued Apr. 26, 1988;

61. Gulyas, et al., U.S. Pat. No. 4,758,552, issued Jul. 19, 1988;

62. Schally, et al., U.S. Pat. No. 4,800,191, issued Jan. 24, 1989;

63. Nestor, et al., U.S. Pat. No. 4,801,577, issued Jan. 31, 1989;

64. Folkers, et al., U.S. Pat. No. 4,935,491, issued Jan. 19, 1990;

65. Seproedi, et al., U.S. Pat. No. 4,948,873, issued Aug. 14, 1990;

66. Haviv, et al., U.S. Pat. No. 5,110,904, issued May 5, 1992;

67. Haviv, et al., U.S. Pat. No. 5,140,009, issued Aug. 18, 1992; and

68. Schally, et al., U.S. Pat. No. 5,198,533, issued Mar. 30, 1993.

Particularly preferred LHRH-active peptides and pseudo-peptides forinclusion in formulations of the present invention are the nona- anddecapeptides known by the generic names or designations A-75998,buserelin, decapeptyl, deslorelin, goserelin, histrelin, nafarelin.

A-75998 (Sequence I.D. No. 1 ) is disclosed and claimed in U.S. Pat. No.5,110,904 and has the structural formula:

N-Ac-D-2-Nal¹ -D-4-Cl-Phe² -D-3-Pal³ -Ser⁴ -N-Me-Tyr⁵ -D-Lys(Nic)⁶ Leu⁷-Lys(NIsp)⁸ -Pro⁹ -GlyNH₂ ¹⁰.

Buserelin (Sequence, I.D. No. 2) is disclosed and claimed in U.S. Pat.No. 4,024,248 and has the structural formula:

5-Oxo-Pro¹ -His² -Trp³ -Ser⁴ -Tyr⁵ -D-Ser (O-(1,1-dimethylethyl))⁶ -Leu⁷-Arg⁸ -ProNHEt⁹.

Decapeptyl (Sequence I.D. No. 3) has the structural formula:

5Oxo-Pro¹ -His² -Trp³ -Ser⁴ -Tyr⁵ -D-Trp⁶ -Leu⁷ -Arg⁸ Pro⁹ -GlyNH₂ ¹⁰.

The preparation of deslorelin (Sequence I.D. No. 4) is disclosed in U.S.Pat. No. 4,071,622 and has the structural formula:

5-Oxo-Pro¹ -His² -Trp³ -Ser⁴ -Tyr⁵ -D-Trp⁶ -Leu⁷ -Arg⁸ -ProNHEt⁹.

Goserelin (Sequence I.D. No. 5) is disclosed and claimed in U.S. Pat.No. 4, 100,274 and has the structural formula:

5-Oxo-Pro¹ -His² -Trp³ -Ser⁴ -Tyr⁵ -D-Ser(O-(1,1-dimethylethyl))⁶ -Leu⁷-Arg⁸ -PronHNHCONH₂ ⁹.

Histrelin (Sequence I.D. No. 6) is disclosed and claimed in U.S. Pat.No. 4,244,946 and has the structural formula: 5-Oxo-Pro¹ -His² -Trp³-Ser⁴ -Tyr⁵ -D-His(N⁹⁶ -Benzyl)⁶ -Leu⁷ -Arg⁸ -ProNHEt⁹.

Lutrelin (Sequence I.D. No. 7) is disclosed in U.S. Pat. No. 4,089,946and has the structural formula:

5-Oxo-Pro¹ -His² -Trp³ -Ser⁴ Tyr⁵ -D-Trp⁶ -N-Me-Leu⁷ -Arg⁸ -ProNHEt⁹.

Nafarelin (Sequence I.D. No. 8) is disclosed and claimed in U.S. Pat.No. 4,234,571 and has he structural formula:

5Oxo-Pro¹ -His² -Trp³ -Ser⁴ -Tyr⁵ -D-2-Nal⁶ Leu⁷ Arg⁸ -Pro⁹ -GlyNH₂ ¹⁰.

In the structural formula presented above, the common three-letterabbreviations have been used for the naturally-occuring amino acids.Where the stereochemistry of the aminoacyl residue is not given, it isunderstood that the residue is that of the naturally occuring L-aminoacid. Aminoacyl residues which are the non-naturally-occuringD-configuration are preceded by a capital letter "D."

The less common abbreviations used in the structural formulae above havethe following meanings:

D-2-Nal denotes a D-3-(naphth-2-yl)alanyl aminoacyl residue;

D-4-Cl-Phe denotes a D-3-(4-chlorophenyl)alanyl aminoacyl residue;

D-3-Pal denotes a D-3-(pyrid-3-yl)alanyl aminoacyl residue;

D-Lys(Nic) denotes a D-lysyl-(N-epsilon-nicotinyl) aminoacyl residue;

Lys(NIsp) denotes a lysyl-(N-epsilon-isoopropyl) aminoacyl residue;

5-Oxo-Pro denotes a 5-oxo-prolyl aminoacyl residue;

D-Ser(O-(1,1-dimethylethyl)) denotes an O-t-butyl-D-seryl aminoacylresidue;

D-His(N⁹⁶ -Benzyl) denotes a D-histidyl aminoacyl residue substituted bya benzyl group on the 1-position of the imidazole ring;

Renin inhibitor compounds suitable for incorporation into sublingualformulations in accordance with the present invention are disclosed inthe following United States Patents which are incorporated herein byreference:

69. Veber, et al., U.S. Pat. No. 4,384,994, issued May 24, 1983;

70. Boger, et al., U.S. Pat. No. 4,470,971, issued Sep. 11, 1984;

71. Boger, et al., U.S. Pat. No. 4,477,440, issued Oct. 16, 1984;

72. Boger, et al., U.S. Pat. No. 4,477,441, issued Oct. 16, 1984;

73. Vebner, et al., U.S. Pat. No. 4,474,941, issued Oct. 30, 1984;

74. Veber, et al., U.S. Pat. No. 4,478,826, issued Oct. 23, 1984;

75. Cazaubon, et al., U.S. Pat. No. 4,481,192, issued Nov. 6,

1984;

76. Boger, et al., U.S. Pat. No. 4,485,099, issued Nov. 27, 1984;

77. Hansen, et al., U.S. Pat. No. 4,510,085, issued Apr. 9, 1985;

78. Hansen, et al., U.S. Pat. No. 4,514,332, issued Apr. 30, 1985;

79. Matsueda, et al., U.S. Pat. No. 4,548,926, issued Oct. 22, 1985;

80. Pinori, et al., U.S. Pat. No. 4,560,505, issued Dec. 24, 1985;

81. Riniker, et al., U.S. Pat. No. 4,595,677, issued Jun. 17, 1986;

82. Hoover, U.S. Pat. No. 4,599,198, issued Jul. 8, 1986;

83. Evans, et al., U.S. Pat. No. 4,609,64 1, issued Sep. 2, 1986;

84. Szelke, et al., U.S. Pat. No. 4,609,643, issued Sept. 2, 1986;

85. Fuhrer, et al., U.S. Pat. No. 4,613,676, issued Sep. 23, 1986;

86. Ryono, et at., U.S. Pat. No. 4,616,088, issued Oct. 7, 1986;

87. Ryono, et al., U.S. Pat. No. 4,629,724, issued Dec. 16, 1986;

88. Bock, et at., U.S. Pat. No. 4,636,491, issued Nov. 3, 1987;

89. Luly, et al., U.S. Pat. No. 4,645,759, issued Feb. 24, 1987;

90. Szelke, et al., U.S. Pat. No. 4,650,661, issued Mar. 17, 1987;

91. Luly, et al., U.S. Pat. No. 4,652,551, issued Mar. 24, 1987;

92. Izuka, et at., U.S. Pat. No. 4,656,269, issued Apr. 7, 1987;

93. Baran, et al., U.S. Pat. No. 4,657,931, issued Apr. 14, 1987;

94. Boger, et al., U.S. Pat. No. 4,661,473, issued Apr. 28, 1987;

95. Bock, et al., U.S. Pat. No. 4,663,310, issued May 5, 1987;

96. Boger, et at., U.S. Pat. No. 4,665,052, issued May 12, 1987;

97. Evans, et al., U.S. Pat. No. 4,665,055, issued May 12, 1987;

98. Ryono, et at., U.S. Pat. No. 4,665,193, issued May 12, 1987;

99. Raddatz, et al., U.S. Pat. No. 4,666,888, issued May 19, 1987;

100. Boger, et al., U.S. Pat. No. 4,668,663, issued May 26, 1987;

101. Boger, et al., U.S. Pat. No. 4,668,770, issued May 26, 1987;

102. Hoover, U.S. Pat. No. 4,668,769, issued May 26, 1987;

103. Luly, et al., U.S. Pat. No. 4,680,284, issued Jul. 14, 1987;

104. Yamato, et al., U.S. Pat. No. 4,683,220, issued Jul. 28, 1987;

105. Matsueda, et al., U.S. Pat. No. 4,698,329, issued Oct. 6, 1987;

106. Thaisrivongs, U.S. Pat. No. 4,703,846, issued Nov. 10, 1987;

107. Holzman, et at., U.S. Pat. No. 4,709,010, issued Nov. 27,

1987;

108. Izuka, et al., U.S. Pat. No. 4,711,958, issued Dec. 8, 1987;

109. Szelke, et at., U.S. Pat. No. 4,713,445, issued Dec. 15, 1987;

110. Raddatz, et al., U.S. Pat. No. 4,721,776, issued Jan. 26, 1988;

111. Hansen, et al., U.S. Pat. No. 4,722,922, issued Feb. 2, 1988;

112. Wagnon, et al., U.S. Pat. No. 4,725,580, issued Feb. 16, 1988;

113. Luly, et al., U.S. Pat. No. 4,725,583, issued Feb. 16, 1988;

114. Luly, et at., U.S. Pat. No. 4,725,584, issued Feb. 16, 1988;

115. Buhlmayer, et al., U.S. Pat. No. 4,727,060, issued Feb. 23, 1988;

116. Bindra, et al., U.S. Pat. No. 4,729,985, issued Mar. 8, 1988;

117. Hudspeth, et al., U.S. Pat. No. 4, 735,933, issued Apr. 5, 1988;

118. Boger, U.S. Pat. No. 4,743,584, issued May 10, 1988;

119. Hudspeth, et al., U.S. Pat. No. 4,743,585, issued May 10, 1988;

120. Wagnon, et al., U.S. Pat. 4,746,648, issued May 24, 1988;

121. Bindra, et al., U.S. Pat. No. 4,749,687, issued Jun. 7, 1988;

122. Gordon, U.S. Pat. No. 4,749,781, issued Jun. 7, 1988; .

123. Raddatz, et al., U.S. Pat. No. 4,755,592, issued Jul. 5, 1988;

124. Natarajan, et al., U.S. Pat. No. 4,757,050, issued Jul. 12, 1988;

125. Buhlmayer, et al., U.S. Pat. No. 4,758,584, issued Jul. 19, 1988;

126. Kaltenbronn, et al., U.S. Pat. No. 4,804,743, issued Feb. 14, 1989;

127. Boger, et al., U.S. Pat. No. 4,812,442, issued Mar. 14, 1989;

128. Raddatz, et al., U.S. Pat. No. 4,812,555, issued Mar. 14, 1989;

129. Hoover, et al., U.S. Pat. No. 4,814,342, issued Mar. 21, 1989;

130. Bender, et al., U.S. Pat. No. 4,818,748, issued Apr. 4, 1989;

131. Patel, U.S. Pat. No. 4,820,691, issued Apr. 11, 1989;

132. Luly, et al., U.S. Pat. No. 4,826,815, issued May 2, 1989;

133. Sham, U.S. Pat. No. 4,826,958, issued May 2, 1989;

134. Raddatz, et al., U.S. Pat. No. 4,829,053, issued May 9, 1989;

135. Rosenberg, et al., U.S. Pat. No. 4,837,204, issued Jun. 6, 1989;

136. Patchett, et al., U.S. Pat. No. 4,839,357, issued Jun. 13, 1989;

137. Wagnon, et al., U.S. Pat. No. 4,840,935, issued Jun. 20, 1989;

138. Iizuka, et al., U.S. Pat. No. 4,841,067, issued Jun. 20, 1989;

139. Luly, et al., U.S. Pat. No. 4,845,079, issued Jul. 4, 1989;

140. Iizuka, et al., U.S. Pat. No. 4,853,463, issued Aug. 1, 1989;

141. Wanger, et al., U.S. Pat. No. 4,855,286, issued Aug. 8, 1989;

142. Hoover, U.S. Pat. No. 4,855,303, issued Aug. 8, 1989;

143. Rosenberg, et al., U.S. Pat. No. 4,857,507, issued Aug. 15, 1989;

144. Hoover, et al., U.S. Pat. No. 4,859,654, issued Aug. 22, 1989;

145. Fuhrer, et al., U.S. Pat. No. 4,863,903, issued Sep. 5, 1989;

146. Iizuka, et al., U.S. Pat. No. 4,863,904, issued Sep. 15, 1989;

147. Hudspeth, et al., U.S. Pat. No. 4,863,905, issued Sep. 15, 1989;

148. Thaisrivongs, et al., U.S. Pat. No. 4,864,017, issued Sep. 5, 1989;

149. Huang, et al., U.S. Pat. No. 4,874,745, issued Oct. 17, 1989;

150. Hester, et al., U.S. Pat. No. 4,880,781, issued Nov. 14, 1989;

151. Hudspeth, et al., U.S. Pat. No. 4,895,834, issued Jan. 23, 1990;

and

152. Fung, et al., U.S. Pat. No. 5,268,374, issued Dec. 7, 1993.

Preferred renin inhibitors for incorporation into sub-lingual dosageformulations of the present invention are enalkiren, zankiren, A-74273,and A-74403.

The preparation of enalkiren and its use as a renin inhibitor aredisclosed in U.S. Pat. No. 4,845,079. and has the name:

H-((beta, beta, dimethyl)beta-Ala-4-(CH₃O)-Phe-His-(2S-amino-1-cyclohexyl3R,4S-dihydroxy-6-methylheptane.

The preparation of zankiren and its use as a renin inhibitor aredisclosed in published European Patent Application No. EP 456 189,published Nov. 13, 1991. Zankiren has the chemical name:

2S-2-Benzyl-3-((1-methylpiperazin-4-yl)sulfonyl)propionyl-4-Thial-(2S-amino1-cyclohexyl-3R,4S-dihydroxy-6-methylheptane.

The preparation of A-74273, and A-74403 and their use as renininhibitors are disclosed in U.S. Pat. No. 5,268,374.

A-74273 has the chemical name:

2S,1S-(4-methoxymethoxypiperidin-1-yl)carbonyl-2-phenylethoxyhexanoicacid amide of-3-(4-morpholinyl)propyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropylhexanamide.

A-74403 has the chemical nameN-(1S)-(4-(methoxymethoxypiperidin-1-yl)carbonyl)-2-phenylethyl-L-norleucylamide of3-(4-morpholinyl)propyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropylhexanamide.

C5a agonists and antagonists suitable for incorporation into sublingualformulations in accordance with the present invention are disclosed inthe following United States Patents which are incorporated herein byreference:

152. Hahn, U.S. Pat. No. 4,692,511, issued Sep. 8, 1987;

153. Luly, et al., U.S. Pat. No. 5,190,922, issued Mar. 2, 1993; and

154. Kawai, et al., U.S. Pat. No. 5,223,485, issued Jun. 29, 1993.

The compositions of this invention comprise the therapeutic agentdissolved or dispersed in a carder which comprises a solvent, anoptional cosolvent, an optional hydrogel, and an oral mucosal membranetransport enhancing agent. The solvent comprises from about 20 percentw/v to about 95 percent w/v, preferably from about 55 percent w/v toabout 80 percent w/v of the carrier of a non-toxic alcohol. Non-toxicalcohols useful in the formulations of the present invention areselected from those well known in the art and include ethanol,isopropanol, stearyl alcohol, propylene glycol, polyethylene glycol(preferably having a molecular weight of up to about 650 daltons), andthe like. Non-toxic alcohols for use in pharmaceutical formulations arewell known in the an (of., for example, "Handbook of PharmaceuticalExcipients", pub. by the American Pharmaceutical Association and ThePharmaceutical Society of Great Britain (1986)). Preferably, thenon-toxic alcohol is ethanol. Most preferably, the non-toxic alcohol isethanol and is present at a concentration of about 80 percent w/v of thecarrier.

The cosolvent is selected from water or a pharmaceutically acceptableoil. Suitable oils for use in the compositions of this invention includemineral oil, Neobee® oil, olive oil, sunflower oil, corn oil, peanut oiland the like.

Hydrogels suitable for use in the compositions of this invention includehydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodiumcarboxymethylcellulose (CMC), polyacrylic acid, poly(methyl methacrylicacid), and the like. When present in the compositions of this invention,the hydrogel comprises from about 0.1 to about 50 percent w/v of thecarrier.

The oral mucosal membrane transport enhancing agent is included in thecompositions of the present invention to facilitate the absorption ofthe therapeutic agent across the mucosal tissues in the oral cavity anddirectly into the blood stream of the subject. Tissue transportenhancing agents suitable for use in the present compositions areselected from essential or volatile oils or from non-toxic,pharmaceutically acceptable inorganic and organic acids.

Essential or volatile oils which may be employed in the compositions areselected from peppermint oil, spearmint oil, menthol, pepper oil,eucalyptus oil, cinnamon oil, ginger oil, fennel oil, dill oil and thelike. The essential or volatile oil, when employed as the oral mucosalmembrane transport enhancing agent in the compositions of the presentinvention is present in a concentration ranging between about 0.5percent w/v and 50 percent w/v of the carrier. The preferred essentialoil is peppermint oil, present in a concentration of between about 1percent w/v and 5 percent w/v of the carrier.

Suitable inorganic and-organic acids are selected from hydrochloricacid, phosphoric acid, aromatic and aliphatic monocarboxylic ordicarboxylic acids of from two to thirty carbon atoms such as aceticacid, citric acid, lactic acid, oleic acid, linoleic acid, lauric acid,palmitic acid, benzoic acid, salicylic acid, and the like. By the term"aromatic" carboxylic acid is meant any acid which contains the6-membered carbocyclic (phenyl) ring system, and by the term "aliphatic"carboxylic acid is meant any acid which contains a straight-chain orbranched chain saturated or unsaturated hydrocarbon backbone. Thepreferred organic acid in compositions of this invention is benzoicacid. Liquid compositions containing benzoic acid are known to enhancethe bioavailability of polypeptides in such compositions whenadministered sublingually (See Example 3).

When the compositions of the present invention contain an acid as theoral mucosal membrane enhancing agent, the pH of the composition rangesbetween about pH 2.0 and pH 7.0, preferably between about pH 4.0 andabout pH 7.0. The pH of the compositions may be adjusted or maintainedby the use of pharmaceutically acceptable, non-toxic buffer systemsgenerally known in the art. The selection of a particular acid isdependent inter alia upon the nature of the anionic component of theacid. Thus, the subject being administered the liquid composition of theinvention may be in need of phosphate, chloride, lactate and the like.Conversely, the administration of a particular anion may becontraindicated in some subjects. The concentration of acid in theliquid compositions of the present invention is dependent upon thenature of the acid (i.e., pk and dissociation constant) as well as thedesired pH. When the acid is benzoic acid, a preferred concentration isfrom about 4 to about 10 percent by weight.

The liquid composition can be formulated into a liquid spray, a liquiddrop, a gel or a paste. The desired consistency is achieved by includingin the liquid composition one or more hydrogels, substances that absorbwater and produce gels of varying viscosity. Hydrogels suitable for usein pharmaceutical preparations are well known in the art. See, e.a.,Handbook of Pharmaceutical Excipients, pub. by The AmericanPharmaceutical Association and The Pharmaceutical Society of GreatBritain (1986) and Handbook of Water-Soluble Gums and Resins, ed. by R.L. Davidson, McGraw-Hill Book Co., New York, N.Y. (1980).

Suitable hydrogels for use in the compositions of this invention includehydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodiumcarboxymethyl cellulose, polyacrylic acid, poly(methyl methacrylic acid)(PMMA). Preferred hydrogels are cellulose ethers such ashydroxyalkylcellulose and hydroxyalkylalkylcellulose compounds. Apreferred hydroxyalkylcellulose is hydroxypropyl cellulose.Hydroxypropyl cellulose is commercially available in a wide range ofviscosity grades sold under the tradename Klucel™ (Hercules, Ltd.,London, England). The concentration of the hydroxyalkylcellulose isdependent upon the particular viscosity grade used and the desiredviscosity of the liquid composition. For example, where the desiredviscosity is less than about 1000 centipoise (cps), hydroxypropylcellulose having an average molecular weight of about 60,000 daltons(i.e., Klucel EF™) can be used. Where the desired viscosity is fromabout 1000 to about 2500 cps, higher viscosity grades of hydroxypropylcellulose can be used (i.e., Klucel LF™ and Lucel GF™). Preferably, theconcentration of hydroxypropyl cellulose is from about 1 to about 5percent w/v and, more preferably from about 2 to about 3 percent w/v ofthe carrier.

Hydroxyalkylalkylcellulose ethers are a class of water-soluble hydrogelsderived from etherification of cellulose. As used herein in reference tothis class of hydrogels, the term "alkyl" means C₁ -C₆ alkyl where alkylrefers to linear or branched chains having 1 to 6 carbon atoms, whichcan be optionally substituted as herein defined. Representative alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyland the like.

Exemplary hydroxyalkylalkylcelluloses are hydroxypropylmethyl cellulose,hydroxyethylmethyl cellulose and hydroxybutylmethyl cellulose.Hydroxypropylmethyl cellulose (HPMC) is preferred. HPMC is commerciallyavailable (i.e., Aldrich Chem. Co., Ltd. Dorset, England and Dow Chem.Co., Midland, Mich., USA) in a wide range of viscosity grades. Inaddition to increasing viscosity, hydroxyalkylalkylcelluloses can serveas a stabilizing, suspending and emulsifying agent. The concentration ofhydroxyalkylalkylcellulose in a liquid composition of this invention isdependent inter alia on its intended use (i.e., stabilizer, emulsifier,viscosity-increasing agent) and its viscosity grade.

In one preferred embodiment of the present invention, the fomulationcomprises between 1 mg/ml and 100 mg/ml of an agent effective to controlthe release of leutenizing hormone releasing hormone or apharmaceutically acceptable salt thereof; a carrier comprising betweenabout 55 and about 80 percent w/v ethanol, about 2 to about 5 percentw/v of hydroxypropyl cellulose hydrogel; and an oral mucosal membranetransport enhancing agent comprising about 10 and about 25 percent w/vbenzoic acid; all percentages based upon the total volume of carrier.

In another preferred embodiment of the present invention, theformulation comprises between 1 mg/ml and 100 mg/ml of an agenteffective to control the release of leutenizing hormone releasinghormone or a pharmaceutically acceptable salt thereof; a carriercomprising between about 55 and about 80 percent w/v ethanol, about 2 toabout 5 percent w/v of hydroxypropyl cellulose hydrogel; and an oralmucosal membrane transport enhancing agent comprising between about 5and about 20 percent w/v benzoic acid and between about 1 to about 5percent w/v peppermint oil; all percentages based upon the total volumeof carrier.

In another aspect, the present invention comprises a method ofsublingually administering a therapeutic agent, preferably apolypeptide, to a patient comprising preparing a liquid composition ofsaid therapeutic agent and an aqueous-alcohol solvent having from about20 to about 95 percent by volume of a non-toxic alcohol and a pH fromabout 4.0 to about 7.0 and administering an effective amount of saidliquid composition to the underside of the tongue of said patient. Theliquid compositions contemplated for use in this method are those setforth above.

The liquid composition is administered to the patient under the tongue.The sublingual mucosae, located on the underside of the tongue, provideexpeditious entry of the polypeptide-containing liquid composition intothe general bloodstream through the sublingual tributary veins. Thetherapeutic agent is first absorbed through the sublingual mucosae intothe sublingual veins. From there, the polypeptide is pumped into theright side of the heart and then into the lungs where the blood isoxygenated. From there the oxygenated blood would carry the therapeuticagent back into the left side of the heart and out through the systemicarteries for distribution throughout the body.

The liquid composition can be administered under the tongue by placingone or more drops underneath the tongue or by spraying the underside ofthe tongue with a preselected volume of the liquid composition.Preferably, the administered volume, either drops or spray, is less thanabout 1 ml.

The following Examples are provided to enable one skilled in the an topractice the present invention and are merely illustrative of theinvention. They should not be read as limiting the scope of theinvention as it is defined by the appended claims.

EXAMPLE 1 Bioavailability of an LHRH Agonist (Leuprolide (Sequence I.D.No. 9) Acetate) Administered Sublingually in a Formulation of thePresent Invention

The liquid compositions of Table 1 were prepared by dissolving thesynthetic polypeptide leuprolide acetate in the liquid compositions suchthat the leuprolide acetate concentration was about 50 mg/ml. Leuprolideacetate has the formula:

5-oxo-L-prolyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosyl-D-leueyl-L-leueyl-L-arginyl-L-prolyl-ethylamide(Sequence I.D. No. 1 ) monoacetate.

                  TABLE 1                                                         ______________________________________                                        A.      Leuprolide acetate  50     mg/ml.                                             Urea                10%    (w/v)                                              Klucel EF ™      2%     (w/v)                                      B.      Leuprolide acetate  50     mg/ml                                              Benzoic acid        5%     (w/v)                                              Klucel EF ™      2%     (w/v)                                              Ethanol             50%    (v/v)                                      C.      Leuprolide acetate  50     mg/ml                                              Klucel EF ™      2%     (w/v)                                      D.      Leuprolide acetate  50     mg/ml                                              Hydroxypropyl cyclodextrin                                                                        20%    (w/v)                                              Klucel EF ™      2%     (w/v)                                      E.      Leuprolide acetate  50     mg/ml                                              Ethanol             80%    (v/v)                                              Klucel EF ™      2%     (w/v)                                      F.      Leuprolide acetate  50     mg/ml                                              Peppermint oil      10%    (v/v)                                              Ethanol             80%    (v/v)                                              Klucel EF ™      2%     (w/v)                                      G.      Leuprolide acetate  50     mg/ml                                              Urea                10%    (w/v)                                              L-arginine HCl      20     mg/ml                                              Klucel EF ™      2%     (w/v)                                      ______________________________________                                    

The liquid compositions were sublingually administered to dogs byplacing 0.1 ml/10 Kg. body weight between the underside of the tongueand the bottom of the oral cavity. In this way, each dog received a doseof leuprolide acetate equal to 0.5 mg/kg. body weight. The plasma levelof leuprolide was determined before and 0.25, 0.5, 1, 2, 4, and 6 hoursafter sublingual administration of the liquid compositions. The resultsof these studies are summarized in FIG. 1 and Table 2.

                  TABLE 2                                                         ______________________________________                                        Composition                                                                   From Table 1                                                                             AUC (0-6 hours)                                                                            % Bioavailability*                                    ______________________________________                                        A          34           2.1                                                   B          318          19.4                                                  C          51           3.1                                                   D          17           1.1                                                   E          353          21.5                                                  F          1385         84.5                                                  G          21           1.3                                                   ______________________________________                                         *Bioavailability is calculated based on iv data                          

In this and subsequent Examples, bioavailability is calculated andexpressed either in terms of Area Under Curve (AUC) or as percent (%)bioavailability. AUC is determined by calculating the area under thecurve of plots of time (X-axis) versus plasma concentration (Y-axis) ofthe administered polypeptide. Typically, AUC is determined over a 6(0-6) or 8 (0-8) hour period. Percent bioavailability is calculated asthe ratio ##EQU1## Increases in AUC and/or bioavailability indicateincreased bioavailability of the administered polypeptide.

The data in FIG. 1 and Table 2 show that ethanol in concentrations from50 (compositions B, Table 1) to 80 percent by volume (compositions E andF, Table 1) increased the bioavailability of sublingually administeredleuprolide.

EXAMPLE 2 Effects of Ethanol on Bioavailability of a SublinguallyAdministered LHRH Agonist (Leuprolide (Sequence I.D. No. 9) Acetate ) inFormulations of the Present Invention

These studies were designed to test the effects of ethanol concentrationon the bioavailability of sublingually administered leuprolide acetate.Liquid compositions comprising 2 percent by weight peppermint oil, 2.5percent by weight Klucel LFTM, 50 mg/ml leuprolide acetate and anaqueous-alcohol solvent having 0, 50, 65 or 80 percent by volume ethanolwere prepared.

Aliquots of these liquid compositions (0.1 ml/10 Kg. body weight) weresublingually administered to anesthetized dogs using a drop or spraydispenser. Plasma levels of leuprolide were measured by RIA in venousblood samples before and 0.33, 0.67, 1, 2, 3, 4, 6 and 8 hours afteradministration. The results of these studies are shown in FIG. 2 andTable 3.

                  TABLE 3                                                         ______________________________________                                        Ethanol (%)                                                                   (w/v)         Bioavailability (%)*                                            ______________________________________                                        80            8.7                                                             65            5.0                                                             50            2.0                                                              0            2.0                                                             ______________________________________                                         *Bioavailability was calculated based on the sc absorption.              

The data in FIG. 2 and Table 3 show that ethanol concentration causes adose-dependent increase in the bioavailability of sublinguallyadministered leuprolide.

EXAMPLE 3 Effects of pH on the Bioavailability of a SublinguallyAdministered LHRH Agonist (Leuprolide (Sequence I.D. No.9) Acetate in aFormulation of the Present Invention

Liquid compositions were prepared to comprise 50 mg/ml leuprolideacetate, 2.5 percent by weight HPMC, an aqueous-alcohol solvent having80 percent by volume ethanol and 0, 5 or 10 percent by weight benzoicacid. The pH's of liquid compositions having 0, 5 or 10 percent byweight benzoic acid were about 6.8, 5.6 and 4.4 respectively. Theresults of these studies are shown in FIG. 3. The data in FIG. 3 showthat the bioavailability of leuprolide is directly proportional tobenzoic acid concentration. Additional studies were performed to showthat the effects of benzoic acid on bioavailability were due to changesin pH rather than an inherent property of benzoic acid per se. Liquidcompositions comprising 50 mg/ml leuprolide acetate, 2 percent by weightpeppermint oil, an aqueous-alcohol solvent having 65 percent by volumeethanol and 4 percent by weight benzoic acid were prepared. In one suchcomposition the pH value was adjusted to a value of about 7.0 with NaOH.In another such composition, the pH value was not adjusted and was about5.6.

The liquid compositions were sublingually administered to dogs (0.1ml/10 kg body wt) and the plasma levels of leuprolide measured over 8hours. The results of this study are summarized in Table 4.

                  TABLE 4                                                         ______________________________________                                               Peppermint                                                                              Benzoic                                                      Ethanol                                                                              Oil       Acid             Percent                                     (% w/v)                                                                              (% w/v)   (% w/v)  pH      Bioavailability*                            ______________________________________                                        65/35                     6.2     5.0                                         65/35  2                  6.2     16.9                                        65/35  2         4        5.6     24.5                                        65/35  2         4        7.0     2.7                                                                   (Adjusted)                                          ______________________________________                                         *Bioavailability was calculated based on the sc absorption.              

The data in Table 4 show that the enhanced bioavailability associatedwith benzoic acid is a function of pH.

EXAMPLE 4 Effects Of Peppermint Oil On The Bioavailability of aSublingually Administered LHRH Agonist (Leuprolide (Sequence I.D. No. 9)Acetate in Formulations of the Present Invention

Liquid compositions comprising 50 mg/ml leuprolide acetate, anaqueous-alcohol solvent having 80 percent by volume ethanol and 0, 0.5,2, 2.5, 5 and 10 percent by volume peppermint oil were prepared andsublingually administered to dogs at a dose of 0.1 ml/10 kg body weight.Plasma leuprolide levels were monitored for 8 hours followingadministration. The results of this study are shown in FIG. 4.

The data in FIG. 4 show that peppermint oil at a concentration of about2 to 10 percent by volume increases the bioavailability of sublinguallyadministered leuprolide acetate.

EXAMPLE 5 Bioavailability of Sublingually Administered LHRH Antagonist(Deslorelin (Sequence I.D. No. 4) in Formulations of the PresentInvention

The synthetic polypeptide Deslorelin™ (Sigma Chem Co., St. Louis, Mo.),pGlu-His-Trp-Ser-Tyr-D-TrpLeu-Arg-Pro-NHET (Sequence ID No. 4), wasdissolved in either saline or a liquid composition comprising 2 percentby volume peppermint oil, 2.5 percent by weight Klucel LFTM™,4 percentby weight benzoic acid and an aqueous-alcohol solvent having 65 percentby volume ethanol such that the concentration of Deslorelin™ was about68mg/ml. About 0.1 ml of the Deslorelin™ compositions were sublinguallyadministered to anesthetized dogs and the plasma level of Deslorelin™measured by RIA immediately before and 0.33, 0.67, 1, 2, 3, 4, 6 and 8hours after administration.

Where dogs received Deslorelin™ in saline, the maximum plasma levelobserved was about 1.5 ng/ml and the AUC (0-8 hours) was about 2hr-ng/ml. In marked contrast, dogs receiving Deslorelin™ in a liquidcomposition of the present invention had a maximum plasma Deslorelin™level of about 290 ng/ml and an AUC (0-8 hours) of about 800 hr-ng/ml.These data show that a liquid composition of this invention markedlyincreases the bioavailability of sublingually administered Deslorelin™.

    __________________________________________________________________________    SEQUENCE LISTING                                                              (1) GENERAL INFORMATION:                                                      (iii) NUMBER OF SEQUENCES: 9                                                  (2) INFORMATION FOR SEQ ID NO:1:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="XAA at position 1 is an                         N-acetyl-D-3- (naphth-2-yl)alanyl residue."                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 2                                                               (D) OTHER INFORMATION: /note="XAA at position 2 is a                          D-3-(4- chloro)phenylalanyl residue."                                         (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 3                                                               (D) OTHER INFORMATION: /note="XAA at position 3 is a                          D-3-(pyrid-3- yl)alanyl residue."                                             (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 5                                                               (D) OTHER INFORMATION: /note="XAA at position 5 is an                         N- methyltyrosyl residue."                                                    (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="XAA at position 6 is a                          D-lysyl(N- epsilon-nicotinyl) residue."                                       (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 8                                                               (D) OTHER INFORMATION: /note="XAA at position 8 is a                          lysyl(N- epsilon-isopropyl) residue."                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                       XaaXaaXa aSerXaaXaaLeuXaaProGly                                               1510                                                                          (2) INFORMATION FOR SEQ ID NO:2:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                    (ix) FEATURE:                                                                (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="XAA at position 1 is a                          5-oxoprolyl residue."                                                         (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="XAA at position 6 is a                          D-seryl(O-t- butyl) residue."                                                 (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 9                                                               (D) OTHER INFORMATION: /note="XAA at position 9 is a                          prolyl N- ethylamide residue."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                       XaaHisTrpSerTyrXaaLeuArgXaa                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:3:                                              (i) SEQUENCE CHARACTERISTICS:                                                  (A) LENGTH: 10 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="XAA at position 1 is a                          5-oxoprolyl residue."                                                         (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="XAA at position 6 is a                          D-tryptyl residue."                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                       XaaHisTrpSerTyrXaaLeuArgProGly                                                1510                                                                          (2) INFORMATION FOR SEQ ID NO:4:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="XAA at position 1 is a                          5-oxoprolyl residue."                                                         (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="XAA at position 6 is a                          D-tryptyl residue."                                                           (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 9                                                               (D) OTHER INFORMATION: /note="XAA at position 9 is prolyl                     N-ethylamide residue."                                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                      XaaHisTrpSerTyrXaaLeuArgXaa                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:5:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                    (ix) FEATURE:                                                                (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="XAA at position 1 is a                          5-oxoprolyl residue."                                                         (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="XAA at position 6 is a                          D-seryl(O-t- butyl) residue."                                                 (i x) FEATURE:                                                                (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 9                                                               (D) OTHER INFORMATION: /note="XAA at position 9 is a                          prolyl azaglycylamide residue."                                               (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                       XaaHisTrpSerTyrXaaLeuArgXaa                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:6:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="XAA at position 1 is a                          5-oxoprolyl residue."                                                         (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="XAA at position 6 is a                          histidyl N- tau-benzyl) residue."                                             (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 9                                                               (D) OTHER INFORMATION: /note="XAA at position 9 is a                          prolyl N- ethylamide residue."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                       XaaHisTrpSerTyrXaaLeuArgXaa                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:7:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="XAA at position 1 is a                          5-oxoprolyl residue."                                                         (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="XAA at position 6 is a                          D-tryptyl residue."                                                           (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 7                                                               (D) OTHER INFORMATION: /note="XAA at position 7 is an                         N-methyl leucyl residue."                                                     (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 9                                                               (D) OTHER INFORMATION: /note="XAA at position 9 is a                          prolyl N- ethylamide residue."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                       Xa aHisTrpSerTyrXaaXaaArgXaa                                                  15                                                                            (2) INFORMATION FOR SEQ ID NO:8:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="XAA at position 1 is a                          5-oxoprolyl residue."                                                         (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="XAA at position 6 is a                          D-3-(naphth- 2-yl)alanyl residue."                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                       XaaHi sTrpSerTyrXaaLeuArgProGly                                               1510                                                                          (2) INFORMATION FOR SEQ ID NO:9:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                    (ix) FEATURE:                                                                (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="XAA at position 1 is a                          5-oxoprolyl residue."                                                         (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="XAA at position 6 is a                          D-leucyl residue."                                                            (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 9                                                               (D) OTHER INFORMATION: /note="XAA at position 9 is a                          prolyl-N- ethylamide residue."                                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                       XaaHisTrpSerTyrXaaLeuArgXaa                                                   15                                                                        

We claim:
 1. A pharmaceutical composition for the sublingual or buccaladministration of a peptide or modified peptide, said modified peptidesmodified by incorporation of non-naturally occurring amino acidresidues, said peptides and modified peptides of twenty amino acids orless, comprisinga) from about 1 to about 100 mg/ml of said peptide ormodified peptide, b) a pharmaceutically acceptable carrier comprising asolvent system comprising from about 20 percent w/v to about 95% w/v ofa non-toxic alcohol and from about 0.5% w/v to about 50% w/v of an oralmucosal membrane enhancing agent; said percentages based upon the totalvolume of career;with the proviso that said peptide or modified peptideis not leuprolide.
 2. A pharmaceutical composition as defined by claim 1wherein said peptide or modified peptide is selected from agonists andantagonists of LHRH.
 3. A pharmaceutical composition as defined by claim1 wherein said peptide or modified peptide.
 4. A pharmaceuticalcomposition as defined by claim 2 wherein said peptide or modifiedpeptide is selected from the group consisting ofN-Ac-D-2-Nal¹-D-4-Cl-Phe² -D-3-Pal³ -Ser⁴ -N-Me-Tyr⁵ -D-Lys(Nic )⁶ -Leu⁷ -Lys(NIsp)⁸-Pro⁹ -GlyNH₂ ¹⁰ (Sequence I.D. No. 1); 5-Oxo-Pro¹ -His² -Trp³ -Ser⁴-Tyr⁵ -D-Ser(O-(1,1-dimethylethyl))⁶ -Leu⁷ -Arg⁸ -ProNHEt⁹ (SequenceI.D. No. 2); 5-Oxo-Pro¹ -His² -Trp³ -Ser⁴ -Tyr⁵ -D-Trp⁶ -Leu⁷ -Arg⁸ Pro⁹-GlyNH₂ ¹⁰ (Sequence I.D. No.3); 5-Oxo-Pro¹ -His² -Trp³ -Ser⁴ -Tyr⁵-D-Trp⁶ -Leu⁷ -Arg⁸ -ProNHEt⁹ (Sequence I.D. No. 4); 5-Oxo-Pro¹ -His²-Trp³ -Ser⁴ -Tyr⁵ -D-Ser(O-(1,1-dimethylethyl))⁶ -Leu⁷ -Arg⁸-PronHNHCONH₂ ⁹ (Sequence I.D. No.5); 5-Oxo-Pro¹ -His² Trp³ -Ser⁴ -Tyr⁵-D-His(Nτ-Benzyl )⁶ -Leu⁷ -Arg⁸ -proNHEt⁹ (Sequence I.D. No.6);5-Oxo-Pro¹ -His² -Trp³ -Ser⁴ -Tyr⁵ -D-Trp⁶ -N- Me-Leu⁷ -Arg⁸ -ProNHEt⁹(Sequence I.D. No.7); and 5-Oxo-Pro¹ -His² -Trp³ -Ser⁴ -Tyr⁵ -D-2-Nal⁶-Leu⁷ Arg⁸ -Pro⁹ -GlyNH₂ ¹⁰ (Sequence I.D. No.8).
 5. A pharmaceuticalcomposition as defined by claim 3 wherein said peptide or modifiedpeptide is selected from the group consisting ofH-((beta, beta,dimethyl)beta-Ala-4-(CH₃O)-Phe-His-(2S-amino-1-cyclohexyl-3R,4S-dihydroxy-6-methylheptane;2S-2-Benzyl-3-((1-methylpiperazin-4-yl)sulfonyl)propionyl-4-Thial-(2S-amino-1-cyclohexyl-3R,4S-dihydroxy-6-methylheptane; 2S,1S-(4-methoxymethoxypiperidin-1-yl)carbonyl-2-phenylethoxyhexanoic acidamide of3-(4-morpholinyl)-propyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropylhexanamide;and N-(1S)-(4-(methoxymethoxypiperidin-1-yl)carbonyl)-2-phenylethyl-L-norleucylamide of3-(4-morpholinyl)propyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropylhexanamide.6. A pharmaceutical composition as defined by claim 1 wherein thepharmaceutically accept carrier further comprises from about 5 percentw/v to about 80 percent w/v of a cosolvent selected from the groupconsisting of water or a pharmaceutically acceptable mineral orvegetable oil, based upon the volume of pharmaceutically acceptablecarrier.
 7. A pharmaceutical composition as defined by claim 1 furthercomprising between about 0.1 and about 50 percent w/v of a hydrogel. 8.A pharmaceutical composition as defined by claim 1 wherein the alcoholis present in an amount ranging between about 55 percent w/v and about80 percent w/v of the pharmaceutically acceptable carrier.
 9. Apharmaceutical composition as defined by claim 1 wherein the non-toxicalcohol is selected from ethanol, propylene glycol, and poly(ethyleneglycol) having a molecular weight of up to about 650 daltons.
 10. Apharmaceutical composition as defined by claim 1 wherein said oralmucosal membrane transport enhancing agent comprises from about 2percent w/v and about 20 percent w/v of said carrier.
 11. Apharmaceutical composition as defined by claim 1 wherein said mucosalmembrane transport enhancing agent is selected from the group consistingof peppermint oil, spearmint oil, menthol, pepper oil, eucalyptus oil,cinnamon oil, ginger oil, fennel oil, and dill oil, hydrochloric acid,phosphoric acid, acetic acid, citric acid, lactic acid, oleic acid,linoleic acid, lauric acid, palmitic acid, benzoic acid, and salicylicacid.
 12. A pharmaceutical composition as defined by claim 4comprisinga) between 1 mg/ml and 100 mg/ml of said peptide or modifiedpeptide b) a pharmaceutically acceptable carrier comprising;1) betweenabout 55 and about 80 percent w/v ethanol, 2) about 2 to about 5 percentw/v of hydroxypropyl cellulose hydrogel; and c) an oral mucosal membranetransport enhancing agent comprising about 10 and about 25 percent w/vbenzoic acid;all percentages based upon the total volume of carrier. 13.A pharmaceutical composition as defined by claim 4 comprisinga) between1 mg/ml and 100 mg/ml of said peptide or modified peptide b) apharmaceutically acceptable carrier comprising1) between about about 55and about 80 percent w/v ethanol, 2) about 2 to about 5 percent w/v ofhydroxypropyl cellulose hydrogel; and c) an oral mucosal membranetransport enhancing agent comprising between about 5 and about 20percent w/v benzoic acid and between about 1 to about 5 percent w/vpeppermint oil;all percentages based upon the total volume of carrier.